Transport in the Circulation Cellular Uptake and Turnover

Folate circulates in the blood predominantly as 5-methylTHF. A variable proportion circulates freely or bound either to low-affinity protein binders such as albumin, which accounts for about 50% of bound folate, or to a high-affinity folate binder in serum, which carries less than 5% of circulating folate. The physiological importance of serum binders is unclear, but they may control folate distribution and excretion during deficiency.

Though most folate is initially taken up by the liver following absorption, it is delivered to a wide variety of tissues in which many types of folate transporters have been described. Because these transporters have affinities for folate in the micromolar range, they would not be saturated by normal ambient concentrations of folate. Therefore, folate uptake into tissues should be responsive to any increases in serum folate levels arising from folate supplementation. An important determinant of folate uptake into cells is their mitotic activity, as would be expected given the dependence of DNA biosynthesis on folate coenzyme function. Folate accumulation is more rapid in actively dividing cells than in quiescent cells, a factor that is probably related to the induction and activity of folylpoly-7-glutamate synthase. This enzyme catalyzes the addition of glutamate by 7-peptide linkage to the initial glutamate moiety of the folate molecule. Although polyglutamate derivatization may be considered a storage strategem, this elongation is the most efficient coenzyme form for normal one-carbon metabolism. The activity of folylpoly-7-glutamate synthase is highest in the liver, the folate stores of which account for half of the estimated 5-10 mg adult complement. Retention within the cell is facilitated by the high proportion of folate associated with proteins, and this is likely to be increased in folate deficiency.

The mobilization of liver and other stores in the body is not well understood, particularly in deficiency states, though some accounts describe poor turnover rates in folate-depleted rats. Transport across cell membranes during redistribution requires deconjuga-tion of the large negatively charged polyglutamates. Mammalian 7-glutamylhydrolases that hydrolyze glutamate moieties residue by residue and transpepti-dases that can hydrolyze folylpolyglutamates directly to mono- or di-glutamate forms of the vitamin have been described for a number of tissues. Thus, mammalian cells possess two types of enzyme that can play a key role in folate homeostasis and regulation of one-carbon metabolism: the folylpolyglutamate synthe-tase that catalyzes the synthesis of retentive and active folate, and a number of deconjugating enzymes that promote the release of folate from the cell. Polyglu-tamate forms released into the circulation either through cell death or by a possible exocytotic mechanism would be hydrolyzed rapidly by plasma 7-glutamyl-hydrolase to the monoglutamate form.

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